1. Field of the Invention
The present invention relates generally to the fields of immunology and the biochemistry of biological response modifiers. More specifically, the present invention relates to a novel method for the inhibition of tumor necrosis factor and nitric oxide production.
1. Description of the Related Art
For more than 50 years, retinoids (natural and synthetic analogues of vitamin A) have attracted great attention by researchers in dermatology, cancer research, and embryonal development. A principal biological effect of the retinoids is to inhibit the growth and/or induce differentiation of the target cells. However, the mechanism of action of retinoids in producing these biological effects is not well understood.
Macrophages play many roles in diverse physiological processes. Depending on the signal received, mononuclear phagocytes can differentiate and become competent to perform specific sets of functions. An appropriate balance between activation (stimulation) and suppression of macrophage functions is essential. For example, inappropriate regulation of activation, by virtue of excess stimulation or insufficient suppression, can lead to extensive tissue injury and damage. This tissue damage, at times, may be so destructive that the survival of the host is threatened. Sites of inflammation, containing mononuclear phagocytes, frequently exhibit extensive damage to normal cells and tissue. In addition, the mechanisms by which macrophages injure and destroy the replicating cells of microbial or neoplastic origin, can also be turned against host cells. Many of the observed biological responses to invasive stimuli, triggered by infectious or neoplastic diseases, are mediated by host-secreted cytokines, in particular, the secreted products of activated macrophages.
Retinoids have been shown by several investigators to modulate the growth and differentiation functions of mononuclear phagocytes. For example, ATRA has been shown to downregulate the production of interferon by phytohaemagglutinin or anti-thymocyte globulin stimulated lymphocytes. Both IL-1 and IL-3 production was induced in vitro in human peripheral blood mononuclear cells and murine WEHI-3 cell lines, respectively, in the presence of retinoic acid in a dose-dependent manner. More recently, an augmenting effect of retinoic acid and 13-cis retinoic acid on IL-1 production by murine keratinoyctes was observed. Induction of IL-1 receptors in EL-4 cells and IL-2 receptors on activated human thymocytes was observed following the culture of these cells in presence of retinoic acid. Furthermore, transforming growth factor (TGF-.beta..sub.1) protein as well its receptor can both be induced in HL-60 (promyelocytic leukemia) cells following their differentiation with retinoids. On the other hand, retinoic acid has been shown to down modulate the transcription of epidermal growth factor-receptor in human epidermoid carcinoma ME180 cells. Similarly, high concentrations of ATRA inhibit the production of interferon by L-929 cells infected with New Castle-disease virus.
Tumor necrosis factor-.alpha. (TNF), a cytokine produced primarily by activated macrophages, has been implicated as an important mediator of the inflammatory response and plays an important role in cancer, cachexia, septic shock, immunomodulation and differentiation. TNF exerts these multiple effects by binding to specific receptors on target cells through two different TNF receptors with molecular masses of about 60 kDa (p60) and 80 kDa (p80). Although most cells express both receptors, their relative abundance varies among different cell types. The p60 form of the TNF receptor is more prevalent on epithelial cells, whereas the p80 receptor is more abundant on cells of myeloid origin.
Nitric oxide (NO-), a highly reactive free-radical produced by the activated macrophages, has emerged as another important mediator of inflammatory responses. TNF in combination with nitric oxide and/or other cytokines (such as interleukin-1 and interleukin-6) may bring about the tissue destruction observed in certain autoimmune diseases such as psoriasis, rheumatoid arthritis, osteoarthritis and other joint diseases.
The prior art remains deficient in the lack of effective methods of inhibiting the production of tumor necrosis factor and nitric oxide. Moreover, the prior art is deficient in the lack of an effective method to treat pathophysiological states characterized by undesirable levels of tumor necrosis factor or nitric oxide in the body.